Post on 15-May-2020
Agonist and Bispecific IgM:Nature’s Approach to Highly Avid, Multivalent Antibodies
Bruce Keyt, Ph.D.Chief Scientific Officer, IGM Biosciences
Mountain View, CA7
PEGS EuropeNovember 22, 2019
IgM: Natural multi‐valent, high avidity antibody
• IgM hexamer (minus J chain) IgM pentamer (plus J chain)
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J‐chain (joining chain)
HC, LC and J‐chains 10 binding sitesHC and LC 12 binding sites
IgM for high aviditytumor cell binding
IgM Structure: Hexamer and Pentamer’3D imaging’ with transmission electron microscopy
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Hexamer (minus J chain) Pentamer (plus J chain)
Ramesh Baliga and NanoImaging
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Bispecific IgM: CD20 x CD3Highly Avid, Asymmetric IgM Antibodies
High AvidityEnhanced binding, to difficult or rare targets with high specificity, high affinity binding domains
Rigid and polarized disc shape confers biophysical propertiesEnhanced control of T cell engagement
Platform for multi‐specific mAbsEnables construction of protein based ”nano‐machines”
Modified J‐chain bispecific IgM10:1 asymmetric binding of tumor cell and T cells, Rapid innovation with various J chain constructs
Conformational change upon bindingEnables specialized properties upon bindingCan be designed to drive forceful agonistic properties
Naturally occurring formatKey to minimize immunogenicity
Daniel Chen PEGS Europe Nov 21, 2019
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Cross‐linking Receptors on Tumor CellsTrimerizing Death Receptor: DR5 / TNFrSF10
MULTIMERIZEDRECEPTOR
MULTIMERIZINGLIGAND
Goal: Destroy tumor cells by trimerizing death receptor 5
Gastric Adenocarcinoma
Colon Adenocarcinoma
DR5 Expression
Also: pancreatic, lung, breast andprostate tumors, leukemia and lymphoma
Trivalent binding required
• Must bind three or more DR5 receptors to send strong signal
Signals cell to commit suicide (apoptosis)
• May be used with many other drugs or checkpoint antibodies
• Cell debris may help immune system cells recognize cancer (APC)
IgGs are bivalent
• Multiple IgG DR5 antibodies tested in clinical trials
Safe, but not effective*
• IgGs can only bind two DR5 receptors
• Cellular cross-linking required for IgG to have any effect
• Breast
• Prostate
• Colon
• Pancreatic
• Leukemia
• Lymphoma
Tumor Expression
* Holland, Cytokine & Growth Factor Reviews, 25 (2014) pp. 185-193
Death Receptor 5 (DR5): Tumor Apoptosis
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TNFrSF Members IgG Antibodiesless effective
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Death Receptor 5: Broad Tumor Expression
Beatrice Wang, Tasnim Kothambalwala, etal
Surface DR5 expression across several tumor cell lines. Cell lines were stained with 2 mg/ml of anti‐DR5‐APC antibody and receptor expression levels were measured by flow cytometry.
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DR5 IgM: CHO cell derived antibody characterization
Beatrice Wang , etal
IgM
Superior Cross‐linking function: Antibody induced Apoptosis DR5 Binding DR apoptosis and cell death
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Antibody (ng/ml)
IgG
1000 x improved apoptosison TNFrSF tumor target
Percent V
iability
1000x
Antibody (pg/ml)
100 x improved binding onlow expression tumor target
0.01 0.1 1 10 100
Percent B
ound
IgGIgM100x
Superior agonist cross‐linking of receptors IgM: 1000 x more potent, multiple antibodies, different DR5 epitopes
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mAb 1
mAb 3
mAb 2
mAb 4
In Vitro Cytotoxicity KineticsIgM rapidly destroys tumor cells, direct apoptotic effect
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Untreated Anti‐DR5 IgG Anti‐DR5 IgM
0.001 0.01 0.1 1 10 100 1000 100000
20
40
60
80
100
120
Colo205 (colon)
[Anti-DR5] (ng/mL)
0.001 0.01 0.1 1 10 100 1000 100000
20
40
60
80
100
120
HCT-15 (colon)
[Anti-DR5] (ng/mL)0.001 0.01 0.1 1 10 100 1000 100000
20
40
60
80
100
120
Nalm-6 (B-ALL)
[Anti-DR5] (ng/mL)
0.001 0.01 0.1 1 10 100 1000 100000
20
40
60
80
100
120
MIA-PaCa-2 (pancreas)
[Anti-DR5] (ng/mL)
In Vitro Cytotoxicity: IgG, crosslinked IgG vs IgMIgM is potent on IgG insensitive cell lines
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IgG
Crosslinked IgGIgM
IgG, CrosslinkedIgG
IgM
IgG, CrosslinkedIgG
IgM
IgG
Crosslinked IgGIgM
IgG‐sensitive tumor cells:
IgG‐resistant tumor cells:
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In Vitro Cytotoxicity: IgG, crosslinked IgG vs IgM
Beatrice Wang, Tasnim Kothambalwala
Significantly Enhanced Efficacy: Tumor Killing vs. IgG in Mouse Models
Durable efficacy seen even in disseminated acute lymphoblastic leukemia
Anti‐DR5: IgM Superior In Vivo to IgG
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Nearly complete tumor eradication in colorectal tumor model
Anti‐DR5 IgM
Anti‐DR5 IgG at 6 g/ml *
Resistant Colorectal Tumor Model (HCT15)
IgM slowed tumor growth better than chemotherapy IgG not synergistic with chemotherapy
Anti‐DR5 IgM Outperforms Standard of Care
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IgG drug exposure is 7x greater than IgM
Colorectal Tumor Model (HCT15 Tumor Cells)
IgM synergistic with chemotherapy and showed dramatically enhanced survival in xenograft tumor model
Anti‐DR5: IgM Synergistic With Irinotecan
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In vivo efficacy yields tumor eradicationIgM efficacy in larger established tumors
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Dosing (3 mg/kg) designed to achieve similar plasma levels of antibody, both for IgG and IgM.Treatment during the first week only
In Vivo EfficacyIgM efficacy in patient‐derived xenograft models
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VehicleAnti‐DR5 IgGAnti‐DR5 IgM
Anti‐DR5 IgG
Anti‐DR5 IgM
DR5: IGM‐8444 In vivo mouse xenograft study
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In Vivo EfficacyDR5‐IgM antibodies penetrate tumors and rapidly induce apoptosis after a single dose
DR5-IgM DR5-IgGCleaved Caspase-3 at 1 hourColo205 Tumors
IgG
OX40: modest efficacy reported with agonist monotherapyBivalent IgG has limited ability to crosslink OX40 cell surface receptors
OX40 IgM Induces More Checkpoint Signaling
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1 10 100 1000 10000
Anti‐OX40 antibody (ng/mL)
600
400
200
0
NFkBactiv
ity(relative luminescence)
GITR IgM Inhibits Effect of Regulatory T Cells
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0
200
400
600
800
IFN- Production
In presence of Tregs: CD4+ proliferation, cytokine secretion
IGM Biosciences: Agonistic Anti‐DR5 IgM • IgM is a naturally occurring multi‐valent, high avidity antibody• Potent cell surface receptor cross‐linking agent• Robust agonist activity with TNFrSF receptors• Strong apoptosis with potent tumor cell killing (EC50 = 1 pM)• DR5 IgM has good anti‐tumor activity, in vitro and in vivo models• Anti‐DR5 IgM effective in solid and liquid tumors• Additive or synergistic activity with chemotherapy• Safety demonstrated in non‐GLP studies with cyno monkeys• High yield cell line development, in progress• IND: in preparation for 2020
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Mode Target Indications
Phase of Development Anticipated MilestonesDiscovery Preclinical Phase 1 Phase 2 Phase 3
T cell EngagerIGM‐2323
(CD20 x CD3)NHL, CLL Phase 1 for R/R
B cell NHL: 2019
Receptor Cross‐linking
Agonist
IGM‐8444(DR5)
Solid andHematologicMalignancies
IND filing: 2020(anticipated)
Targeted Cytokines IL‐15 x PD‐L1
Solid andHematologicMalignancies
IND filing: 2021(anticipated)
Lead Programs
IGM Biosciences: Oncology Pipeline
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Acknowledgments
325 East Middlefield Road Mountain View, CA 94043 26
Immuno‐Oncology• Angus Sinclair• Beatrice Wang
‐ Tasnim Kothambawala ‐ Ling Wang
• Dalya Rosner‐ Susan Calhoun
• Manal Amoury
Preclinical Sciences• Steve Carroll
‐Maya Leabman‐ Yuan Cai‐ Chitra Saraiya
Discovery Biology• Ramesh Baliga• Paul Hinton
‐ Kevin Carlin• Dean Ng
‐ Sachi Rahman‐ Yasinee Ng
• Keyu Li• Marigold Manlosuc
Process Sciences • Marvin Peterson
‐ Bing Shan‐ Avneesh Saini‐ Hongjun Yue‐Madeline Tran
Clinical R&D• Daniel Chen‐Wayne Godfrey‐ Iris Sison‐ Genevive Hernandez